Lysine-rich histone (H1) is a lysyl substrate of tissue transglutaminase: Possible involvement of transglutaminase in the formation of nuclear aggregates in (CAG)(n)/Q(n) expansion diseases
Ajl. Cooper et al., Lysine-rich histone (H1) is a lysyl substrate of tissue transglutaminase: Possible involvement of transglutaminase in the formation of nuclear aggregates in (CAG)(n)/Q(n) expansion diseases, DEV NEUROSC, 22(5-6), 2000, pp. 404-417
Histone H1,which contains about 27% lysine, is an excellent lysyl donor sub
strate of Ca2+-activated guinea pig liver tissue transglutaminase as judged
by rapid fluorescence enhancement in the presence of the glutaminyl-donor
substrate 1-N-(carbobenzoxy-L-glutaminylglycyl)-5-N-(5'N'N'-dimethytaminona
phthelenesulfonyl)diamidopentane, Sodium dodecyl sulfate get electrophoresi
s of a 30-min reaction mixture revealed the presence of fluorescent high-M-
r aggregates, which are also formed when histone H1 is incubated solely wit
h activated tissue transglutaminase. Aggregate formation is even more prono
unced when histone H1 is incubated with activated tissue transglutaminase a
nd dimethylcasein (glutaminyl donor only). The findings suggest not only th
at histone H1 is an especially good lysyl substrate of tissue transglutamin
ase, but that it is also a glutaminyl substrate. Histone H1 is a good lysyl
substrate of transglutaminase purified from Streptoverticillium mobaraense
, suggesting that the ability of histone H1 to act as a transglutaminase ly
syl substrate is widespread. In agreement with previous studies, it was fou
nd that human P-endorphin is a moderately good substrate of tissue transglu
taminase. At least 8 neurodegenerative diseases, including Huntington's dis
ease, are caused by (CAG)(n) expansions in the genome and by an expansion o
f the corresponding polyglutamine domain within the expressed, mutated prot
ein. Polyglutamine domains are excellent substrates of river and brain tran
sglutaminases. A hallmark of many of the (CAG)(n)/polyglutamine expansion d
iseases is the presence of polyglutamine-containing aggregates within the c
ytosol and nuclei of affected neurons. Transglutaminase activity occurs in
both of these compartments in human brain. In future studies, it will be im
portant to determine whether transglutaminases play a role in (1)cross-link
ing of histone H1 to glutaminyl donors (including polyglutamine domains) in
nuclear chromatin, (2) the formation of nuclear aggregates in (CAG)(n)/pol
yglutamine expansion diseases, (3) DNA laddering and cell death in neurodeg
enerative diseases and (4) depletion of neuropeptides in vulnerable regions
of Huntington's disease brain. Copyright (C) 2000 S. Karger AG. Basel.